Xnxco



United States PatentlQ 2,749,343 Pat'ent'ed' June 5, 1956 I Claims priority, application Switzerland February 6, 1953 4 Claims. (Cl. 260-2564) The present invention is concerned with new nuclear substituted 4-amino-uracils as well as processes for the production thereof.

It has been found that nuclear substituted 4-aminouracils (1.3.5-trisubstituted 2.6-dioxo-4-amino-tetrahydropyrimidines) of the general formula:

R1NCO Rz-N- -NH: I wherein R1, R2 and R3 each represents a member selected from the group consisting of ethyl and n-propyl radicals, have an excellent diuretic action on being administered per os. They can be produced easily by various methods. Thus, N.N'-disubstituted ureas of the general formula:

R2NHCO-NHR1 II can be condensed with tit-substituted cyanoacetic acids of the general formula:

NC-CH-COOII a III if necessary with the help of a condensation agent such as, e. g. acetic anhydride, to form trisubstituted cyanoacetyl ureas of the general formula:

These can then be converted into the end products of the general Formula I by treating with alkaline substances. If the alkyl radicals R1 and R2 differ from each other, mixtures of isomeric compounds with regard to the substituents of the endocyclic nirogen atoms are obtained, whereby the isomer with the ethyl group in position 1, i. e. R1 predominates.

The N.N-disubstituted ureas of the general Formula II which are necessary as starting materials are N.N-diethyl urea, N-ethyl-N'-propyl urea and N.N'-di-n-propyl urea which are known and can be easily obtained by reacting ethyl or propyl amine with ethyl or propyl isocyanate; compounds with both substituents alike can also be obtained by reacting 1 mol of phosgene with 2 mols of ethylamine or n-propylamine respectively.

The a-substituted cyanoacetic acids of the general Formula III are the a-ethyland the a-n-propyl cyanoacetic acids.

A single homogeneous reaction product, also with R1 and R2 dilfering from each other and also products wherein R1 represents an n-propyl and R2 an ethyl group can be obtained if the trisubstituted cyanacetyl ureas of the general Formula IV serving as intermediate products are produced by reacting cyanaceto-N-alkylamides of the general formula:

Rr-NH-CO lli general formula:

2' general formula:

00' Its-1 1 VI A further modification of the process first above men- .tioned consists in condensing in an anhydrous medium in the presence ofalkaline condensation agents such as e. g. sodium alcoholates, N.N-disubstituted ureas of the general Formula II with esters, in particular the ethyl or methyl esters, of a-substituted cyanacetic acids of the general Formula III to form end products of the general Formula I. I

Further, the new trisubstitutedAmmiuo-uracils can also be produced by introducing the ethyl or n-propyl radical in the 1-position of disubstituted 4-amino-uracils of the with alkyl isocyanates of the RzN-CNH2 VII by treating such 4-amino-uracils with a suitable alkylating agent in the presence of an alkali. Ethyl and propyl bromide or iodide or diethyl sulphate can be used as alkylating agents. The starting material-s of the general Formula VII can be obtained in a manner analogous to that for the corresponding trisubstituted 4-amino-uracils by condensing low molecular monoalkyl or monoalkenyl ureas with a-substituted cyanacetic acids of the general Formula III.

The following examples serve to further illustrate the production of the new compounds. Parts are given as parts by weight and the temperatures are in degrees centigrade.

Example 10.3 parts of 3.5-diethyl-4-amino-uracil (obtained by condensing N-ethyl urea with a-cyano-n-butyric acid) are dissolved in 100 parts of ethyl alcohol. 20 parts of 20% caustic soda lye and 21 parts of n-propyl iodide are added and the whole is boiled under reflux for 3 hours. The alcohol is then distilled off, the syrupy residue is stirred with a little 20% caustic soda lye to remove any unreacted starting product, the lye is poured off, the residue is washed with cold water and finally crystallised from a great quantity of boiling water. After recrystallising from water, 3.5-diethyl-l-n-propyl-4-amino-uracil is obtained as colourless shining crystals which contain 1 mol of crystal water, The crystals melt at about at the crystal water is given off, the product recrystallises at about and melts then instantaneously at 146.

The following compounds for example of the general formula:

can also be prepared by methods described above:

No. R R; R; gg g 1 czHs CrHr 02H; 2 n-CaH1 II-C3H1 CgHs l07-108 3 ll-CsH1 n-CsH7 n-O H1 136-137 3 cornstarch, lactose, stearic acid, talc, magnesium stearate, 4. The compound of the formula n-CaHr-N-CO What I cla1m 1s: C 1. Nuclear substituted 4-amino-uracils of the general formula: 5 11C;Hr-N-&NHI

g" References Cited in the file of this patent OI C-Rr UNITED STATES PATENTS h R R d b l d 2,567,651 Papesch et al Sept. 11, 1951 w erem 1, 2 an a eac represent a mem er se ecte from the group consisting of ethyl and n-propyl radicals. OTHER REFERENCES 2, The compound of th formula Kattus: Bull. Johns Hopkins Hosp., v01. 89, pp. 1-8

CHHFCO (July 1951 CsHr-N- -NH: 3. The compound of the formula 11-0 .Hr-N-o 0 O l-C 1H;

n-CzHr-N-C-NH: 

1. NUCLEAR SUBSTITUTED 4-AMINO-URACILS OF THE GENERAL FORMULA: 